Apixaban 5mg Twice Daily and Clinical Outcomes in Patients With Atrial Fibrillation and Advanced Age, Low Body Weight, or High Creatinine
A Secondary Analysis of a Randomized Clinical Trial

Background

In patients with atrium fibrillation (AF), reduced doses of oral anticoagulation are recommended for those with increased predicted exposure and a related increased risk of bleeding. However, reduced doses of NOACs are more frequently used in AF patients than expected [1,2].

In the ARISTOTLE trial (Apixaban forReduction of Stroke and Other Thromboembolic
Complications in Atrial Fibrillation trial), apixaban 5 mg twice daily versus warfarin was studied in AF patients. A reduced dose of apixaban (2.5 mg twice daily) was used in patients with 2 or more of the following dose-reduction criteria: age ≥ 80 years; weight ≤ 60 kg; creatinine levels ≥ 1.5 mg/dL [3,4].

In this secondary analysis of the ARISTOTLE study it was assessed whether the effects of apixaban 5 mg twice daily on stroke or systemic embolism and bleeding – compared to warfarin - varied among patients with 1 or no dose-reduction criterion. Moreover, the frequency of dose reduction and the safety of the 5 mg twice daily dose of apixaban compared with warfarin were assessed across the range of individual dose-reduction criteria.

Main results

In the ARISTOTLE trial, 95.4% of patients were randomised to receive apixaban 5 mg twice daily or warfarin. Of these, 76.9% had no dose-reduction criteria and 22.8% had only 1 dose-reduction criterion. Out of the patients with only 1 dose-reduction criterion, 41.3% were ≥ 80 years old, 36.0% weighed ≤ 60 kg, and 22.8% had creatinine levels ≥ 1.5 mg/dL.

However, comparing warfarin to apixaban 5 mg twice daily showed consistently less major bleeding among patients with 1 and no dose-reduction criterion (P for interaction = 0.71). Similar results were seen for each dose-reduction criterion.

Furthermore, there was no evidence of statistical heterogeneity in the effect of apixaban versus warfarin on stroke or systemic embolism (P for interaction = 0.36), ischemic stroke (P for interaction = 0.14), intracranial haemorrhage (P for interaction = 0.26), all-cause death (P for interaction = 0.054) or CV death (P for interaction = 0.26).

Across the range of age, weight, creatinine level and creatinine clearance, apixaban was consistently associated with a numerically lower risk of major bleeding than warfarin.

Conclusion

AF patients with advanced age, or low body weight, or renal dysfunction have a higher risk of stroke or systemic embolism and major bleeding. Although patients with at least two of these criteria received dose-reduction, patients with only one criterion received the standard apixaban dose of 5 mg twice daily. These analysis showed that patients with one criterion have similar benefit of the 5 mg twice daily dose of apixaban – compared to warfarin - as patients without these criteria, with respect to stroke or systemic embolism and bleeding. Therefore, the 5 mg twice daily dose of apixaban should be the preferred dose of apixaban for these patients, in contrast to 2.5 mg twice daily.